Regulation of glucose uptake in mesangial cells stimulated by high glucose: role of angiotensin II and insulin.

Mesangial cells (MCs) play a central role in the pathogenesis of diabetic nephropathy (DN). MC dysfunction arises from excessive glucose uptake through insulin-independent glucose transporter (GLUT1). The role of the insulin-dependent transporter (GLUT4) remains unknown. This study evaluated the effect of high glucose on GLUT1, GLUT4, and fibronectin expression levels. Glucose uptake was determined in the absence and presence of insulin. Angiotensin II has been implicated as a mediator of MC abnormalities in DN, and its effects on the GLUTs expression were evaluated in the presence of losartan. MCs were exposed to normal (NG, 10 mM) or high (HG, 30 mM) glucose for 1, 4, 12, 24, and 72 hrs. Glucose uptake was elevated from 1 hr up to 24 hrs of HG, but returned to NG levels after 72 hrs. HG induced an early (1-, 4-, and 12-hrs) rise in GLUT1 expression, returning to NG levels after 72 hrs, whereas GLUT4 was overexpressed at later timepoints (24 and 72 hrs). HG during 4 hrs induced a 40% rise in glucose uptake, which was unaffected by insulin. In contrast, after 72 hrs, glucose uptake was increased by 50%, only under insulin stimulus. Losartan blunted the effects of HG on GLUT1, GLUT4, and fibronectin expression and on glucose uptake. Results suggest that MCs can be highly susceptible to the HG environment since they uptake glucose in both an insulin-independent and insulin-dependent manner. The beneficial effects of angiotensin II inhibition in DN may also involve a decrease in the rate of glucose uptake by MCs.

Effect of long-term type 1 diabetes on renal sodium and water transporters in rats.

The effects of long-term diabetes in the presence of established nephropathy on tubular function remains poorly understood. We evaluated the levels of the main sodium and water transport proteins expressed in the kidney after long-term (8 weeks) of streptozotocin (STZ)-induced type 1 diabetes mellitus (DM) in untreated (D) and insulin (4 U/s.c./day)-treated (D+I) rats. D animals presented upregulation ( approximately 4.5-fold) of Na/glucose cotransporter (SGLT1), whereas the alpha-subunit of the epithelial sodium channel (alpha-ENaC) and aquaporin 1 (AQP1) were downregulated ( approximately 20 and 30% respectively) with no change in the Na/H exchanger (NHE3), Na/Cl cotransporter (TSC) and AQP2. Insulin replacement partially prevented these alterations and caused increases in the expression of alpha-ENaC and AQP2. These effects suggest an action of insulin in the tubular transport properties. The upregulation of SGLT1 may constitute a mechanism to prevent greater glucose losses in the urine but it may result in glucotoxicity to the proximal epithelial cells contributing to the diabetic nephropathy. The decrease of alpha-ENaC in D animals may compensate for the increased sodium reabsorption via SGLT1 resulting in discrete natriuresis. DM-induced polyuria was not due to changes in AQP2 expression.